Intermediates and processes for producing alpha-lipoic acid



e a anion Patented Sept. 26, 1961 3,002,011 INTERMEDIATES AND PROCESSESFOR PRO- DUCING a-LIPOIC A'CID Frederick W. Holly, Cranford, and ArthurF. Wagner,

Princeton, N.J., assignors to Merck & Co., Inc., Rahway, N.J., acorporation of New Jersey No Drawing. Original application Dec. 4, 1953,Ser. No. 396,333, now Patent No. 2,853,497, dated Sept. 23, 1958.Divided and this application Nov. 23, 1956, Ser. No. 623,823 4 24Claims. (Cl. 260-399) This invention relates to 6,8-dithioloctanoicacid. More particularly, this invention is' concerned with novelprocesses and intermediates useful in the production of6,8-dithioloctanoic acid. 1

In the preparation of the valuable growth stimulating substance calledoc-lipoic acid or 5-[3-(1,2-dithiacyclo. pentyl)] pentanoic acid, it hasbeen found that this substance may be conveniently prepared by oxidationof 6,8-di-thioloctanoic acid to the desired cyclic compound byprocedures disclosed in the J. Am. Chem. Soc. 74, 3455 (1952). However,none of the known methods of producing 6,8-dithioloctanoic acid andrelated .compounds are entirely suitable for this purpose because ofinvolved procedures, low yields and the resulting high cost ofproduction.

Therefore, an object of this invention is to provide novel processes andintermediate compounds which are particularly satisfactory for thesynthetic production of 6,8-dithioloctanoic acid. Another object is toprovide novel chemical compounds of use in the preparation of othervaluable compounds.

It has now been discovered according to one embodiment of the presentinvention that 6,8-dithioloctanoic acid (*IV) may be convenientlyproduced by the process which comprises reducing a 6,8-(hydrocarbonsubstituted mercapto)-5-oxocaprylic acid (I) to produce a6,8-(hydrocarbon substituted mercapto) -5-hydroxycaprylic acid whichcyclizes to the corresponding a-lactone (II), reacting said lactone witha suitable reducing agent to produce a 6,8-(hydrocarbon substitutedmercapto) caprylic acid (III) and subsequently converting said compoundto 6,8-dithioloctanoic acid by reacting it with an agent suitable forcleaving such thioethers. This process may be illustrated as follows:

O OH

H I CHzCHgCHC (0119300 OH-- [CH2CH2CHCH(CHz)aCOOH] wherein R and Rrepresents the same or different hydrocarbon su-bstituents.

The first step in this process comprises reduction of the6,8-(hydrocarbon substituted mercapto) -S-o-xocapyrlic acids to thecorresponding S-hydroxy compounds and B-lactones thereof. To effect thisreduction, ordinary reducing agents such as the borohydride saltsincluding sodium borohydride, sodium trimethoxy borohydride, potassiumborohydride and lithium borohydride are employed. The described reactionis conveniently achieved by contacting the oxocapyrlic acid with asuitable borohydride salt in the presence of a suitable solvent.Generally an excess of the borohydride salt is employed to attainoptimum results. Examples of some solvents in which the reaction can beeffected are aqueous alcohols such as methanol, ethanoland isopropanoland solvents such as tetrahydrofuran, dioxane, isopropylamine, pyridineand water. At ordinary temperatures the reaction proceeds to completionin from about 1 to 3 hours to form an intermediate metal complex.

An acid such as hydrochloric acid or sulfuric acid is added to decomposethe metal complex and produce the desired 6,8-(hydrocarbon substitutedmercapto)-S-hydroxycaprylic acid. Under acidic conditions, however, theresulting hydroxy acid cyclizes to the corresponding fi-lactone andordinarily is isolated in this form. Alternatively, formation of thehydroxy acid structure is achieved by the addition of an alkaline agentsuflicient to produce basic conditions. The presence of a base opens thea-lactone and yields the hydroxy acid as a salt which may be isolated ifdesired. Such products may be isolated by conventional techniques. Thus,the 8-lactone is isolated by extraction of the acidic reaction mixturewith an immiscible solvent such as chloroform and subsequentdistillation.

The 6,-8-(hydrocarbon substituted mercapto) -5-oxo caprylic acids whichcan be reduced in the described manner may have hydrocarbon substituentswhich are the same or different alkyl, alkenyl, alkynyl, aryl andaralkyl groups. This reduction, however, is more readily eifected whensuch hydrocarbon substituents have 8 carbons or less, and in thesynthesis of oc-liPOiG acid, it is preferred to utilize those compoundsin which the hydrocarbon substituents are the same (bis) lower alkyl oralkenyl groups. Examples of compounds which are suitable for use in thisreaction that might be mentioned are6,8-bis(methylmercapto)-5-oxocaprylic acid, 6,8-bis-(ethylmercapto)-5-oxocaprylic acid,6,8-bis(propylmercapto)-5-oxocaprylic acid, 6,8-bis (butylmercapto)-5-oxo caprylic acid, 6,8-bis(phenylmercapto) -5-oxocaprylic acid,6,8-bis(benzylmercapto)-5-oxocaprylic acid, 6,8-bis(allylmercapto)-5-oxocaprylic acid, 6,8-bis(2-methyl-1-ethy1- Z-butenemercapto)-5-oxocapry1ic acid, 6,8-bis(3-methyl-2-ethyl-Z-pentenemercapto)-5-oxocaprylic acid, 6,8-bis-(propargylmercapto)'-5-oxocaprylic acid,6-ethy1-mercapto-8-propy1mercapto-5-oxocaprylic acid the like.

In a specific illustration of this reaction6,8-bis(rnethylmercapto-S-oxocaprylic acid may be reacted with sodiumborohydride and the mixture acidified to obtain 6,8-bis(methylmercapto)-5-hydroxycaprylic acid fi-lactone. Other similarcompounds which may be produced from the appropriate reactants by theapplication of these methodsare6,8-bis(methylmercapto)-5-hydroxycaprylic acid, 6,8-bis(ethylmercapto)-5-hydroxycaprylic acid,6,8-bis(propylmercapto)-5-hydroxycaprylic acid,6,8-bi's(butylmercapto)-5-hydroxycaprylic acid, 6,8-bis(phenylmercapto)-S-hydroxycaprylic acid, 6,8-bis(benzylmercapto)-5-hydroxycaprylic acid,6,8-bis(allylmercapto)-5-hydroxycapryh'c acid,6,8-bis(Z-methyl-1-ethyl-2-butenemercapto)- S-hydroxycaprylic acid,6,8-bis(3-methyl-2-ethyl-2-pentenemercapto)-5-hydroxycaprylic acid,6,8-bis (propargylmercapto) -5-hydroxycaprylic acid,6-ethylrnercapto-8-propylmercapto-S-hydroxycaprylic acid and the likeand o-lactones thereof.

According to the second step in this process the 6,8- (hydrocarbonsubstituted mercapto)-5-hydroxycaprylic acid B-lactone is reduced to thecorresponding 6,8-(hydrocarbon substituted mercapto) caprylic acid. Thisreaction is achieved with any suitable reducing agent and, for thispurpose, phosphorous-iodine has been found/to be particularly useful.The reaction is conveniently efiected by contacting the reactants anacidic medium such as aqueous acetic acid, or aqueous mineral acids suchas hydrochloric and phosphoric acids. Elevated temperatures such as thereflux temperatures are ordinarily used to accelerate the reaction andunder such con ditions, from two to 20 hours is required to complete thereaction. After the reaction has been completed the unreacted iodine isreduced, as by the action of sodium bisulfite, and the product isolatedfrom the mixture by conventional procedures. Thus, the 6,8-(hydrocarbonsubstituted mercapto) caprylic acids may be extracted with chloroform,the organic solution extracted with aqueous sodium bicarbonate,acidified, reextracted into chloroform and the solvent evaporated. Theproduct can be purified by distillation.

Examples of some of the novel compounds which may be prepared accordingto this method from the corresponding 6-lactones are 6,8-(hydrocarbonsubstituted mercapto) caprylic acids wherein the hydrocarbonsubstitucuts are the same or different alkyl, alkenyl, alkynyl, aryl andaralkyl groups such as the compounds 6,8-bis(methylmercapto) caprylicacid, 6,8-bis(ethylmcrcapto) caprylic acid, 6,8-bis(propylmercapto)caprylic acid, 6,8- bis(butylmercapto) caprylic acid,6,8-bis(phenylrnercapto) caprylic acid, 6,8-bis(benzylmercapto) caprylicacid, 6,8-bis(allylmercapto) caprylic acid, 6,8-bis(2-methyl-1-ethyl-Z-butenemercapto) caprylic acid, 6,8-bis(3-methyl-2-ethyl-2-pentenemercapto) caprylic acid, 6,8-bis(propargylmercapto)caprylic acid, 6-ethylmercapto-8-propylmercapto caprylic acid and othersimilar compounds.

Esters of the 6,8-(hydrocarbon substituted mercapto) caprylic acids arereadily produced by reacting the caprylic acids with the appropriatealcohol in the presence of a suitable esteritying acid like mineralacids such as hydrochloric acid and sulfuric acid. This reaction is mostconveniently etfccted at slightly elevated temperatures. Isolation ofthe esters is accomplished by the usual procedures such as evaporationof the solvents.

The 6,8-(hydrocarbon substituted mercapto) caprylic acids are alsoesterified by preparing the corresponding acyl halide and reacting itwith an alkanol, aryl alcohol or aralkanol to produce the desired ester.The acyl halides used as intermediates in this process may be preparedby reacting a 6,8-(hydrocarbon substituted mercapto) caprylic acid witha suitable halogenating agent such as thionyl chloride, oxalyl chloride,phosphorous trichloride, phosphorous tribromide and the like in aconventional solvent or excess of the halogenating agent if liquid. Theacyl halides thus produced are separated from the reaction mixture andesterified by contact with the appropriate alcohol to form the desiredester.

Some of the esters which are produced according to these procedures arethe methyl, ethyl, propyl, benzyl and phenyl esters of the6,8-(hydrocarbon substituted mercapto) caprylic acids previouslydisclosed herein.

In addition, salts of the 6,8-(hydrocarbon substituted mercapto)caprylic acids may also be produced by reacting the acid with an alkalimetal or alkaline earth metal hydroxide, carbonate or bicarbonate. Somesalts which may be produced in this way are the sodium, potassium,lithium, calcium and magnesium salts of the 6,8-(hydrocarbon substitutedmercapto) caprylic acids.

The last step of this process is directed to conversion of the6,8-(hydrocarbon substituted mercapto) caprylic acids to the desired6,8-dithioloctanoic acid. This conversion is conveniently achieved withsuitable ether cleaving agents such as anhydrous or concentrated aqueousmineral acids such as sulfuric acid, hydrochloric acid, hydrobromicacid, hydroiodic acid, phosphoric acid and thiourea hydrohalides such asisothiouronium chloride and bromide. To etfect the reaction thereactants are preferably combined and heated at an elevated temperatureup to about 100 C. for 1 to hours. The reaction mixture is then cooled,extracted with a water immiscible solvent such as cloroform and thesolvent evaporated under reduced pressure to obtain the desired6,8-dithioloctanoic acid.

According to a further embodiment of the present invention the6,8-bis(alkenyl or aralkyl substituted mercapto) caprylic acids areconverted to 6,8-dithioloctanoic acid by hydrogenolysis with an alkalimetal in liquid ammonia. This reaction may be illustrated as follows:

S R S R SH 811 II I IV wherein R and R represent alkenyl and aralkylgroups.

The reaction is conveniently effected by adding the caprylic acid toliquid ammonia at about its boiling point and subsequently adding analkali metal such as sodium, potassium or lithium to the resultingmixture. The reaction goes to completion quickly to form the desiredproduct. Excess alkali metal is neutralized by the addition of ammoniumsalts and the product is conveniently recovered by allowing the ammoniato boil off. It is purified by acidification and extraction with asuitable solvent such as chloroform. In specific illustrations of thisprocess 6,8-bis(ally1mercapto) caprylic acid and 6,8-bis(benzylmercapto)caprylic acid are converted to 6,8-dithioloctanoic acid by reaction withsodium in liquid ammonia.

According to another embodiment of the present invention there isprovided 5-hydroxy-5-[3-(1,2-dithiacyclopentyl)]pentanoic acid which maybe briefly called S-hydroxy a-lipoic acid, and processes for preparingthis and novel intermediate compounds useful in these processes.

It is now found that S-hydroxy-S[3-(l,2-dithiacyclopentyl)]pentanoicacid and its B-lactone is obtained by treating a 6,8-bis(alkenyl oraralkyl mercapto)-S-hydroxycaprylic acid or d-lactone thereof (II) withan alkali metal in liquid ammonia to produce5-hydroxy-6,8-dithioloctanoic acid or the fi-lactone thereof (V) andoxidizing said compound to produce the desired dithiacyclo compound(VI). This process may be illustrated as follows in which the e-lactonesare employed as reactants and obtained in the process, but it isunderstood that the process is equally operable with the hydroxy acids:

wherein R and R represent alkenyl and aralkyl groups.

The production of 5-hydroxy-6,8-dithioloctanoic acid and its fi-lactoneis effected by reacting a 6,8-bis(alkenyl or aralkylmercapto)-5-hydroxycaprylic acid or its e-lactone with an alkali metalin liquid ammonia. The conditions suitable for achieving this reactionare substantially those which have been previously described in detailhereiuabove in elfecting a similar reaction. The product of the presentreaction is a mixture of the hydroxy acid and 6-lactone structuresalthough under the conditions of reaction the formation of a salt of thehydraxy acid is favored. Ordinarily, however, the product is isolated asthe B-lactone by neutralizing the excess alkali metal, removing ammonia,taking the residue up in aqueous acid and extracting with ether.Examples of some compounds which may be converted to the5-hydroxy-6,8-dithioloctanoic acid and fi-lactone thereof are6,8-bis(allylmercapto) -5-hydroxycaprylic acid and6,8-bis(benzylmercapto)-5-hydroxycaprylic acid and other similarcompounds disclosed herein.

Oxidation of 5-hydroxy-6,8-dithioloctanoic acid or .the a-lactonethereof to 5-hydroxy-5-[3-(1,2-dithiacyclopentyl)]pcntanoic acidor thefi-lactone thereof is conveniently accomplished by treatment with anoxidizing agent such as iodine-potassium iodide. This reaction isreadily achieved in an inert solvent such as.ether at ordinarytemperatures. The reaction goes to completion in a short time. 1Thereaction mixture is then treated in the usual ways to recover theproduct. Thus, the mixture may be treated with sodium bisulfite toreduce excess iodine, washed with water and evaporated under reducedpressure to remove the solvent. The product is ordinarily obtained asthee-lactone but under basic conditions the corresponding hydroxy acidmay be obtained.

In the practice of this invention the"6,8--(hydrocarbon substitutedmercapto)-8-oxocaprylic acids used as starting materials may beconveniently preparedaccording to processes disclosed by Wagner in US.patent application Serial No. 369,535 United States Patent No.2,842,587, issued July 8, 1958 and by Holly, Wagner, Walton and Hoffmanin US. patent application Serial No. 396,334 United States Patent No.2,809,978, issued October 15, 1957.

EXAMPLE 1 6,8-bis(methylmercapto)-5-hydroxycaprylic acid fi-lacton About8.5 g. of 6,8-bis (methylmercapto)-5-oxocaprylic acid is dissolved in370 ml. of ethanol and 26 m1. of water is added. The solution is cooledin an ice bath and 6.7 g. of sodium borohydride is'added portionwise.After the initial vigorous reaction has subsided the mixture is allowedto stand at room temperature for two hours. The mixture is acidified topH 3 with concentrated hydrochloric acid, filtered and the filtrateadjusted to pH 8 with 8 N sodium hydroxide; After filtration the ethanolis removed by evaporation under reduced pressure. 100 ml. of water isadded, the pH is adjusted to 3 and the6,8-bis(methylmercapto)-5-hydroxycaprylic acid d-lactone is isolated bychloroform extraction. The chloroform solution is dried over anhydrousmagnesium sulfate, filtered and evaporated to isolate the product. It ispurified by distillation under reduced pressure at a pot temperature of165-190 C. at pressures of 75-300u; N =l.5384l.5398; mol. weight(ebulliometric) 234:2 (calc. 234).

EXAMPLE 2 6,8-bis(ethylmercapto)-5-hydroxycaprylic acid 6-lact0ne SevenIILL'Of Water and 100 ml. of ethanol are combined and 2.5 g. of6,8-bis(ethylmercapto)-5-oxocaprylic acid is added to the mixture. Thesolution is cooled and 2 g. of sodium borohydride is added slowing withstirring. After the reaction is completed the mixture is acidified withsulfuric acid and the fi-la'ctone of6,8-bis(ethylmercapto)-5-hydroxycaprylic acid is thereby obtained. Themixtureis filtered and concentrated under reduced pressure. Theconcentrate is diluted with water, acidified and extracted with ether.The product is obtained by removing the solvent under diminishedpressure.

EXAMPLE 3 6,8-bis(allylm ercapt)-5- hydroxycaprylic acid d-lactone Fiveg. of 6,8-bis(allylmercapto)-5-oxocaprylic acid is dissolved in 220 ml.of dioxane and 40 ml. of water and cooled. To the cooled solution isadded about 4 g. of potassium'borohydride at such a rate as to preventoverheating. After the vigorous reaction has subsided the mixture iswarmed to room temperature and allowed to stand for severalhours. Themixture is acidified with hydrochloric acid, filtered, the adjusted to 7concentrated and extracted with chloroform. The chloroform extract isconcentrated under diminished pressure to remove the solvent. The 6,8-bis(allylmer'capto) 5-hydroxycaprylic acid a-lactone is purified bydistillation under reduced pressure.

7 EXAMPLE. 4

v, 6,8-bis(phenylmercapto)-5- I hydroxycaprylic acid a-lactone j EXAMPLE5 6,8-bis( benzylmercapto) -5- hydroxycap rylic acid a-lactone Four g.of 6,8-bis(benzylmercapto)-5-oxocaprylic acid is dissolved in ml. ofmethanol and 10 ml. of water. The mixture is cooled and 4 g. of sodiumborohydride is added slowly in small portions. The mixture is warmed toroom temperature, and after several hours is acidified with sulfuricacid and filtered. The mixture, adjusted to pH 7, is concentratedunder'reduced pressure, diluted with water and extracted with ether. Theether is removed in vacuo and the6,8-bis(benzylmercapto)-5-hydroxycaprylic acid o-lactone is purified bydistillation under reduced pressure.

EXAMPLE 6 6-methylmercapt0-8-ethylmercapto-S- 1 hydroxycaprylic acidfi-l ctone To a cooled solution of 7 g. of 6-rnethylmercapto-8-ethylmercapto-S-oxocaprylic acid in 300 ml. of methanol and 75 ml. ofwater is added very slowly 6 gm. of sodium borohydride with stirring.Heat is evolved and cooling is continued until the reaction subsides.The mixture is allowed to warm to room temperature gradually and afterseveral hours is acidified with hydrochloric acid to pH 2. Themixture isfiltered, adjusted to pH 7 with sodium hydroxide and filtered. Thefiltrate is concentrated, diluted with water and acidified withhydrochloric acid. The product is extracted with ether and isolated byconcentration under reduced pressure. The 6-methylmercapto-8ethylmercapto 5 hydroxycaprylic acid 6- latcone is recovered as an oil.

EXAMPLE 1 6,8-bis(methylmercapt0) caprylic acid 1.36 g. of6,8-bis(methylmercapto)-5-hydroxycaprylic acid a-lactone is dissolved in25 ml. of glacial acetic acid and 5 ml. of water. To this solution isadded 540 mg. of red phosphorus and 2.21 g. of iodine. The mixture isrefluxed for 17 hours, cooled, filtered and then diluted with ml. ofwater. The excess iodine is reduced by the addition of aqueous sodiumbisulfite and the solution is extracted with chloroform. The chloroformextract is washed with saturated aqueous sodium chloride, dried overanyhdrous magnesium sulfate, and concentrated under reduced pressure toyield 6,8-bis(methylmercapto) caprylic acid.

The methyl ester is prepared by reacting 6,8-bis(methylmercapto)'caprylic acid with phosphorus trichloride to prepare the correspondingacyl chloride which upon reaction with methanol gives the desired methylester. The

ethyl, propyl, benzyl and phenyl esters are prepared in a similarmanner.

Salts of 6,8bis,(methylmercapto) caprylic acid are produced by reactingthe acid with a base such as an alkali metal or alkaline earth metalhydroxide, bicarbonate or carbonate.

EXAMPLE 8 6,8-bis(ethylmercapto) caprylic acid About 0.5 g. of6,8-bis(ethylmercapto)-5-hydroxycaprylic acid B-lactone is added to 20ml. of phosphoric acid (90%) and 3 ml. of water. After adding 0.15 g. ofred phosphorus and 1 g. of iodine the mixture is refluxed for 10 hours.The mixture is cooled, sodium bisulfite added to reduce the iodine andthe mixture is extracted with ether. The ether extract is concentratedto obtain, 6,8-bis(ethylmercapto) caprylic acid. The product is furtherpurified by bicarbonate extraction and by distillation under reducedpressure.

EXAMPLE9 6,8-bis(allylmercapt) caprylic acid To a mixture of 10 ml. ofglacial acetic acid and 1 ml. of water is added 0.45 g. of6,8-bis(allylmercapto)-5 hydroxycaprylic acid a-lactone. The mixture iscooled and 0.1 g. of red phosphorus and 0.5 g. of iodine is added. Afterrefluxing for 6 hours the mixture is cooled, sodium bisulfite is addedto reduce the iodine and the product is extracted with chloroform. Thechloroform solution is extracted with saturated aqueous sodiumbicarbonate and the acidic product is isolated by acidifying to pH 3 andextraction with chloroform. The 6,8-bis(allylmercapto) caprylic acid isisolated by evaporating the solvent.

Other compounds which are prepared by this process by reduction of thecorresponding S-hydroxy procursors are 6,8-bis(benzylmercapto) caprylicacid, 6,8-bis(phenylmercapto) caprylic acid,6-methylmercapto-8-ethylmercapto caprylic acid and6-benzylmercapto-8-methylmercapto caprylic acid.

EXAMPLE 6,8-dithiol0ctan0ic acid from. 6,8-bis(methylmercapt0) caprylicacid About 314 mg. of 6,8-bis(methylmercapto) caprylic acid in 5 ml. of50% aqueoue sulfuric acid is heated at 8 5 C. for 3% hours. The mixtureis then poured into water and the 6,8-dithioloctanoic acid is extractedwith chloroform and concentrated under reduced pressure to isolate theproduct.

Alpha lipoic acid is prepared from the 6,8-dithioloc' tanoic acidproduced above by reacting it in chloroform with aqueous 10%iodine-potassium iodide. The excess iodine is reduced with aqueoussodium bisulfite, the chloroform extract is washed with water, driedover anhydrous magnesium sulfate and concentrated under reduced pressureto isolate the product.

EXAMPLE 11 6,8-dithi0l0ctanoic acid from 6,8-bis(allylmercapto) caprylicacid To 10 ml. of concentrated hydrochloric acid is added 1 gm. of6,8-bis(allylmercapto) caprylic acid and the mixture heated at 50 C. for10 hours. The mixture is cooled, added to water and the'6,8-dithioloctanoic acid extracted with ether. The product is recoveredby evaporating the solvent.

EXAMPLE 12 6,8-dithiol0ctanoic acid from 6,8-bis(benzylmercapto)caprylic acid A concentrated aqueous solution (10 ml.) of phosphoricacid is warmed and to it is added 0.5 g. of 6,8-bis- (benzylmercapto)caprylic acid. The mixture is heated to 100 C. for 2 hours, cooled andwater is added. Re-

covery of 6,8-dithioloctanoic acid is achieved by extraction withchloroform and concentration under reduced pressure.

EXAMPLE 13 6,8-dithialoclanoz'c acid by hydrogenolysis of 6,8-bis(allylmercapto) caprylic acid 5-hydroxy-6,8-dithioloctanoicacid-fi-lactone About 1.2 g. of 6,8-bis(allylmercapto)-5-hydroxycaprylicacid is dissolved in ml. of liquid ammonia and sodium is added in smallportions until the blue color is permanent. The excess sodium isneutralized by the addition of ammonium sulfate to the mixture. Theliquid ammonia is allowed to evaporate, the residue is taken up in 30ml. of water and the solution is acidified to pH 3 with concentratedhydrochloric acid. The mixture is extracted with ether and the5-hydroxy-6,8-dithioloctanoic acid-e-lactone is isolated byevaporationof the solvent.

Its infrared spectrum in carbon tetrachloride solution shows a bondedhydroxyl group in the 34 region and a strong bond at 5.85,a indicativeof the carboxyl group. In addition, the absence of a band at 6.09;.shows complete removal of the allylic groups.

EXAMPLE 15 5-hydroxy-5 [3-(1,2-dithiacyclopentyl)] pentanoicacid-6-lact0ne The 5-hydroxy-6,8-dithioloctanoic acid fi-lactoneproduced as in Example 14 is taken up in ether and oxidized with aqueous10% iodine-potassium iodide. Excess iodine is reduced with aqueoussodium bisulfite. The 5- hydroxy-5[3-(1,2-dithiacyclopentyl)] pentanoicacid-6- lactone is isolated by evaporation of the solvent underdiminished pressure. Its ultra-violet spectrum shows a shoulder at 273 m(5%=12.6) and a plateau at 320 mi (5 %=5.4).

EXAMPLE 16 6,8-dithi0l0ctanoic acid by hydrogenolysis of 6,8-bis(benzylmercapto) caprylic acid To 100 ml. of liquid ammonia is added 0.5g. of 6,8- bis(benzylmercapto) caprylic acid with stirring. Metallicsodium is then added until a blue color persists. When a persistant bluecolor is obtained, ammonium chloride is added to neutralize the excesssodium and the ammonia is removed by evaporation under reduced pressure.50 ml. of water is added to the residue plus sufficient hydrochloricacid to make the solution pH 3. The 6,8-dithioloctanoic acid is isolatedby extraction into chloroform and removal of the organic solvent.

EXAMPLE l7 6,8-dithi0loctan0ic acid from 6,8-bis(methylmcrcapto)caprylic acid 133 mg. of 6,8-bis(methylmercapto) octanoic acid and 500mg. of thiouronium chloride are mixed and heated at C. for one hour. Themixture is cooled to room temperature and 3 ml. of 2.5 N NaOH is added.The solution is heated at 80 C. for ninety minutes. After being cooledto room temperature the mixture is acidified to pH 3 with concentratedhydrochloric acid and extracted with chloroform. The chloroform extractis evaporated to give -6,8-dithioloetanoic acid as a residue.-

9 Various changes and modifications of the invention can be made and tothe extent that such variations incorporate the spirit of this inventionthey are intended to be included within the scope of the appendedclaims.

What is claimed is: 1. Compounds having the formula omornomomhooox SR SRwherein X is selected from the group consisting of alkali and alkalineearth metals, hydrogen, and alkyl, aryl and aralkyl groups having up toeight carbon atoms and R and R' are selected from the class consistingof alkyl, alkenyl, alkynyl, aryl and aralkyl groups having up to eightcarbon atoms.

2. A compound of the formula- OH OHiOHwHzhCOOH SR SR wherein R and R areselected from the class consisting of alkyl, alkenyl, alkynyl, aryl andaralkyl groups having up to eight carbon atoms.

3. A 6,8-bis(lower alkylmercapto)capyrylic acid. 4. A 6,8-bis (loweralkenylmercapto)capry1ic acid. 5. 6,8-bis(methylmercapto)caprylic acid.6. 6,8-bis(allylmercapto)caprylic acid. 7. The process which comprisesreacting the fi-lactone of a compound of the formula with phosphorus andiodine to produce a compound of the formula- CHaGHaCH(OH2)4COOH S R S Rwherein R and R are selected from the class consisting of alkyl,alkenyl, alkynyl, aryl and aralkyl groups having up to eight carbonatoms.

8. The process which comprises reacting a 6,8-bis(loweralkylmercapto)-5-hydroxycaprylic acid fi-lactone with a mixture ofphosphorus and iodine to produce the corresponding 6,8-bis(loweralkylmercapto)caprylic acid.

9. The process which comprises reacting a6,8-bis(methylmercapto)-5-hydroxycaprylic acid a-lactone with a mixtureof phosphorus and iodine to produce the correspond ing 6,8-bis(methylmercapto) caprylic acid.

10. The process which comprises reacting a 6,8-bis- (loweralkenylmercapto) -5-hydroxycaprylic acid fi-lactone with a mixture ofphosphorus and iodine to produce the corresponding 6,8-bis(loweralkenylmercapto)capry1ic acid.

11. The process which comprises reacting a6,8-bis(allylmercapto)-5-hydroxycaprylic acid fi-lactone with a mixtureof phosphorus and iodine to produce the corresponding6,8-bis(allylmercapto)caprylic acid.

12. The process which comprises treating a compound of theformulaomomoHwHmOooH S R R with an alkali metal in liquid ammonia toproduce 6,8- dithioloctanoic acid, wherein R and R represent hydrocarbongroups from the class consisting of lower alkenyl and aralkyl groups.

13. The process which comprises reacting a 6,8-bis(hydrocarbonsubstituted mercapto)caprylic acid with a member of the group consistingof non-oxidizing mineral acids and thiourea hydrohalides to form6,8-dithioloctanoic acid.

14. The process which comprises reacting 6,8-bis(methy1mercapto)caprylicacid with sulfuric acid to produce 6 8-dithiol.octanoic acid.

15. The process which comprises reacting 6,8-bis(allylmercapto)caprylicacid with hydrochloric acid to produce 6,8-dithioloctanoic acid.

16. The process which comprises reacting 6,8-bis(benzylmercapto)caprylic acid with phosphoric acid to produce6,8-dithioloctanoic acid.

17. The process which comprises reacting6,8-bis(-methylmercapto)octanoic acid with thiouronium chloride toproduce 6,8-dithioloct-anoic acid.

18. A process which comprises reacting a compound having theformulaoniongomoumooon SR SR wherein R and R are selected from the classconsisting of alkyl, alkenyl, alkynyl, aryl and aralkyl groups having upto eight carbon atoms with an alcohol having the formula ROH wherein Ris selected from the class consisting of alkyl, aryl and aralkyl groupshaving up to eight carbon atoms in the presence of a non-oxidizingmineral acid to produce the corresponding ester having theformulaomoHzomoHmoooR" SR s12 19. A process which comprises reacting acompound having the formula- SR R wherein R and R are selected from theclass consisting of alkyl, alkenyl, alkynyl, aryl and aralkyl groupshaving up to eight carbon atoms with an halogenating agent to producethe corresponding acyl halide having the formula- CHiCHiGHwHmOOY SR Rwherein Y is a halogen.

20. A process which comprises reacting a compound having the formula- OHCHzCEKOHzMCOY SR sR wherein R and R are selected from the classconsisting of alkyl, alkenyl, alkynyl, aryl and aralkyl groups having upto eight carbon atoms and Y is a halogen with an alcohol having theformula R"OH wherein R is lower alkyl to form the corresponding esterhaving the formula- OHiOH CH(GHz)4COOR/ SR SR 21. A process whichcomprises reacting a compound having the formulaoHzornoHwHmoooH SR SRwherein R and R are selected from the class consisting of alkyl,alkenyl, alkynyl, aryl and aralkyl groups having up to eight carbonatoms and Y is a halogen.

23. 6,8-dibenzylmercaptooctanoic acid.

24. The method which comprises subjecting 6,8-dibenzylmercaptooctanoicacid to the action of alkali metal in liquid ammonia until thecorresponding alkali metal salt of 6,8-dimercaptooctanoic acid isproduced.

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1. COMPOUNDS HAVING THE FORMUAL-